Process for the preparation of galanthamine

ABSTRACT

The subject invention concerns a process for the preparation of enantiomerically-enriched galanthamine from racemic galanthamine, and a process for increasing the enantiomeric excess of enantiomerically-enriched galanthamine, by direct crystallization of galanthamine salts.

This application is a 371 of PCT/GB97/00023 filed filed Jan. 6, 1997.

FIELD OF THE INVENTION

This invention relates to processes for the manufacture ofenantiomerically-enriched forms of galanthamine, in free base or saltform.

BACKGROUND TO INVENTION

(-)-Galanthamine and derivatives thereof are useful compounds for thetreatment of Alzheimer's disease and related illnesses. Currentlygalanthamine is usually obtained by extraction from natural sources,such as daffodil or snowdrop bulbs. However, the yields of theseextractive procedures are low, resulting in high costs and limitedsupplies of naturally obtained galanthamine.

It is known that single enantiomer galanthamine (2) can be prepared fromracemic narwedine (1) through resolution followed by reduction of theenone function, as depicted in Scheme 1, below. Usefully, since theenantiomers of narwedine (1) readily equilibrate (racemise) by way ofreversible ring opening to a dienone, coupled to the fact that crystalsof racemic (1) exist as a conglomerate of enantiomers, a dynamicresolution of (1) can be carried out by crystallisation with entrainmentby crystals of the desired isomer (see Barton and Kirby, J. Chem. Soc.(C) (1962) 806). However, in respect of a total synthesis, racemicnarwedine itself is not readily available. ##STR1##

Several procedures have been developed for the resolution ofgalanthamine. One procedure involves formation of a diastereomeric saltwith di-p-toluoyl tartaric acid and separation of the mixture byrecrystallisation; see Kametani et al, Heterocycles, 1976, 1111.However, the need for the unnatural form of tartaric acid to access thedesired, therapeutically-active, (-)-galanthamine renders this processcostly.

Another resolution procedure involves the formation of diastereomericesters with (-)-camphanic chloride and separation of the mixture byrecrystallisation; see Szewczyk et al, J Het. Chem. (1995) 32: 195. Theresultant product is then converted into (-)-galanthamine by reductionin a process which destroys the chiral auxiliary group, so renderingthis process impractical for economic production.

SUMMARY OF THE INVENTION

The present invention is based on the surprising discovery of processesfor the separation of the enantiomers of galanthamine by directcrystallisation techniques.

According to a first aspect of the present invention, a process for thepreparation of an enantiomerically-enriched galanthamine salt, in whichthe counterion is achiral, comprises seeding a supersaturated solutionof the racemic salt with an enantiomerically-enriched form of the salt,and recovering the salt form that crystallises out of solution.

According to a second aspect of the present invention, a process forincreasing the enantiomeric excess of an enantiomerically-enrichedgalanthamine salt, in which the counterion is achiral, comprisescrystallisation of a solution of the said enantiomerically-enrichedsalt, and recovery of the salt form that crystallises out of solution.Optionally, the solution can be seeded with an enantiomerically-enrichedform of the salt. Advantageously, this process for enhancingenantiomeric enrichment can be used subsequent to any process capable ofproducing enantiomerically-enriched galanthamine, to achieve very highenantiomeric excess.

Both the processes of the present invention have the advantage ofsimplicity and cost effectiveness. Preferably, the processes areemployed to manufacture salt forms enriched in (-)-galanthamine, whichcan then be used directly in pharmaceutical formulations, provided ofcourse that the salt counterion is pharmaceutically-acceptable, orconverted to the free base form of galanthamine, eg. by reaction with anappropriate base. However, both processes can adequately be used toprepare salt forms enriched in (+)-galanthamine, or the free basethereof, if this is desired.

DESCRIPTION OF THE INVENTION

In the context of the present Application, by enantiomerically-enrichedtypically we mean at least 10% ee, more typically at least 20% ee, uptowhat may be considered substantially single enantiomer form, forinstance at least 80% ee, and typically at least 90% ee, or higher.

The salt used in the present invention can be any salt which is capableof giving the desired result. Preferably, the salt ispharmaceutically-acceptable, thereby allowing direct incorporation intopharmaceutical formulations, as mentioned above. Most preferably, thesalt is the hydrogen bromide salt, as this is the form in which(-)-galanthamine is currently marketed.

Without being bound by theory, it seems that racemic galanthaminehydrobromide exists as a conglomerate of its enantiomers rather than themore common case where racemates crystallise in space groups containingboth enantiomeric forms. Evidence for the presence of a conglomerate isthat the racemate and the pure enantiomer have identical IR spectra; seeJacques, Enantiomers, Racemates and Resolutions, Krieger, Fla., 1991, p53. Furthermore, (-)-galanthamine hydrobromide shows much lowersolubility than racemic hydrobromide salt in methanol, their respectivesolubilities being 6 mg/ml and 17 mg/ml. Processes for the separation ofconglomerates are well described in the literature (see, for instance,Crosby, chirality in Industry, Wiley, Chichester, 1992 p 24-27).

The racemic galanthamine salt for use in the process according to thefirst aspect of the present invention can be manufactured using standardchemical techniques, in which racemic galanthamine is reacted with amoiety providing the salt counterion. Racemic galanthamine can be madeby, for instance, reduction of racemic narwedine. Theenantiomerically-enriched salt employed as the seed in thecrystallisation process can be prepared from enantiomerically-enrichedgalanthamine obtained from natural sources, or from other syntheticprocedures, as only a small amount of this is required. The enantiomericexcess of the seed is preferably high, for instance at least 90% ee, orhigher, ie. substantially single enantiomer form.

To a degree, the enantiomeric excess that is obtained is dependent uponthe process conditions employed, with optimisation of conditions such astemperature, concentration and solvent allowing higher enantiomericexcess to be achieved.

The process according to the second aspect of the invention can be usedto increase the enantiomeric excess of enantiomerically-enrichedmaterial obtained by way of the process according to the first aspect ofthe invention, or by any other method for preparingenantiomerically-enriched galanthamine, such as classical resolution orreduction of racemic or enantiomerically-enriched narwedine, andconversion to the appropriate salt form. Examples of classicalresolution procedures have been given above. Reduction of (-)-narwedinecan be carried out using any suitable reducing agent, such as lithiumaluminium hydride as described by Barton and Kirby, although this hasthe disadvantage that epigalanthamine is also formed, or L-Selectride,although this reagent tends to be expensive and is only available inpilot plant quantities. Asymmetric reduction of racemic narwedine isdescribed in WO-A-9631453, also in the name of the present Applicant.

Optionally, a seed can be added to aid crystallisation. The seed shouldbe enriched in the desired enantiomer, to direct the crystallisation tothat enantiomer. The enantiomeric excess of the seed can be the same asor different to that of the salt solution to which it is added, butpreferably it is of high enantiomeric excess, eg. at least 90% ee, orhigher.

The increases in enantiomeric excess that are possible using thisprocess again depend to a degree on process condition optimisation, butcan be up to 50% ee or more, providing at least 90% ee, preferably atleast 98% ee, or higher, in the final product.

The processes of the invention may be applicable to galanthaminederivatives also.

The present invention is now illustrated by way of the followingExamples. Example 1 illustrates the process according to the firstaspect of the present invention, and Examples 2 to 5 the processaccording to the second aspect of the invention.

EXAMPLE 1

Racemic galanthamine hydrobromide (101 mg) was dissolved in methanol(4.5 ml) at 60° C. and the solution allowed to cool to 20° C. Seedcrystals of (-)-galanthamine hydrobromide (1 mg) were added and themixture stirred at 20° C. for 4 hours. The mixture was filtered toafford (-)-galanthamine hydrobromide (17 mg) with an enantiomeric excessof 19%.

EXAMPLE 2

(-)-Galanthamine (6.11 g, 68% ee) was dissolved in EtOH (18 ml) bywarming to 35° C. 48% HBr (3 ml, 1.2 equiv.) in EtOH (3 ml) was added,giving a white precipitate. After cooling in ice the solid was collectedby filtration. Yield=6.01 g, (77%), 90% ee.

5.0 g of the (-)-galanthamine.HBr salt obtained was dissolved in H₂ O(10 ml) on heating. (-)-Galanthamine.HBr seed crystals (3 mg) were addedand the mixture cooled to room temperature. The resulting solid wascollected by filtration. Yield=1.7 g (34%), >98% ee.

EXAMPLE 3

(-)-Galanthamine.HBr (3.0 g)(90% ee) was slurried in EtOH (30 ml) atreflux. After 60 min. the mixture was cooled to room temperature, andstirred for 16 hours. Filtration yielded (-)-galanthamine.HBr (2.28 g,76%) of >98% ee.

EXAMPLE 4

(-)-Galanthamine (18.0 g, 81% ee) was dissolved in EtOH (65 ml) bywarming. 48% HBr (8.4 ml) in EtOH (10 ml) was added dropwise. Theresulting white solid was collected by filtration. Yield=22.06 g (96%).

This solid was dissolved in 3:1 IMS:H₂ O (200 ml) on heating to reflux,and then cooled to 5° C. giving a white solid. Recovery of the solidyielded (-)-galanthamine.HBr (17.34 g, 79%), of >99.5% ee.

EXAMPLE 5

(-)-Galanthamine (41.5 g, 44% ee) was dissolved in EtOH (170 ml). 48%HBr (19.4 ml) in EtOH (20 ml) was added dropwise to the solution, givinga white precipitate. This was collected by filtration. Yield of(-)-galanthamine.HBr=48.7 g, 91%.

This material was recrystallised from 3:1 IMS:H₂ O to give a whitesolid. Yield=28.8 g (54%), of 92% ee.

I claim:
 1. A process for the preparation of anenantiomerically-enriched galanthamine salt, in which the counterion isachiral, comprising seeding a supersaturated solution of the racemicsalt with an enantiomerically-enriched form of the salt, and recoveringthe salt form that crystallises out of solution.
 2. The processaccording to claim 1, for the preparation of a salt enriched in the(-)-enantiomer, wherein seeding is with a salt form enriched in the (-)enantiomer.
 3. The process according to claim 1, for the preparation ofa salt enriched in the (+)-enantiomer, wherein seeding is with a saltform enriched in the (+)-enantiomer.
 4. A process for increasing theenantiomeric excess of a first enantiomerically-enriched galanthaminesalt, in which the counterion is achiral, comprising crystallisation ofa solution of the said first enantiomerically-enriched salt, andrecovery of the salt form that crystallises out of solution.
 5. Theprocess according to claim 4, wherein the solution is enriched in the(-)-enantiomer of the salt.
 6. The process according to claim 4, whereinthe solution is enriched in the (+)-enantiomer of the salt.
 7. Theprocess according to claim 1, further comprising seeding the saltsolution with a second enantiomerically-enriched form of the salt,enriched in the desired enantiomer.
 8. The process according to claim 4,wherein the said first enantiomerically-enriched salt is prepared by aprocess as defined in claim
 1. 9. The process according to claim 4,wherein the said first enantiomerically-enriched salt is prepared byclassical resolution of racemic galanthamine, and conversion to the saltform.
 10. The process according to claim 4, wherein the said firstenantiomerically-enriched salt is prepared by asymmetric reduction ofracemic narwedine to give enantiomerically-enriched galanthamine, andconversion to the salt form.
 11. The process according to claim 4,wherein the said first enantiomerically-enriched salt is prepared byreduction of enantiomerically-enriched narwedine to giveenantiomerically-enriched galanthamine, and conversion to the salt form.12. The process according to claim 4, wherein the salt is thehydrobromide.
 13. A process for preparing enantiomerically-enrichedgalanthamine, comprising forming an enantiomerically-enrichedgalanthamine salt using a process according to any preceding claim, andconverting the salt to galanthamine.
 14. The process according to claim13, for preparing galanthamine enriched in the (-)-enantiomer,comprising forming the salt by a process as defined in claim
 2. 15. Theprocess according to claim 13, for preparing galanthamine enriched inthe (+)-enantiomer, comprising forming the salt by a process as definedin claim
 3. 16. The process according to claim 1, wherein the salt isthe hydrobromide.
 17. The process according to claim 13, for preparinggalanthamine enriched in the (-)-enantiomer, comprising forming the saltby a process as defined in claim
 5. 18. The process according to claim13, for preparing galanthamine enriched in the (+)-enantiomer,comprising forming the salt by a process as defined in claim 6.